01Approach to the Critical Patient/attcp55

Immediate priorities

›Airborne isolation and respiratory precautions

›Negative-pressure airborne infection isolation room (AIIR) immediately

›N95 respirator for all entering staff

›Door kept closed at all times

›Surgical mask placed on patient during transport

›Minimum respiratory hygiene until isolation confirmed

›Public health notification initiated if TB suspected

›Mandatory reportable disease in all jurisdictions

Critical presentations requiring immediate stabilization

›Massive hemoptysis

›Definition: >300 mL blood per 24 hours

›Risk of airway flooding and hemorrhagic shock

›Immediate airway assessment

›Positioning: affected side dependent if lateralized

›Facilitates drainage away from good lung

›Bronchoscopy or interventional radiology for bronchial artery embolization

›First-line for massive hemoptysis

›Tranexamic acid 1 g IV over 10 minutes

›Consider for active hemoptysis

›Miliary TB with ARDS

›ARDS mortality 47-58% in adults with miliary TB

›Mechanical ventilation with lung-protective strategy

›Tidal volume 6 mL/kg ideal body weight

›PEEP titration to maintain SpO2 >=92%

›High-flow nasal cannula as bridge if not intubated

›Urgent anti-TB therapy initiation despite critical illness

›Delay worsens outcomes significantly

02History/hx90

Cardinal symptoms

›Persistent cough

›Duration >=2-3 weeks is cardinal screening threshold

›Productive or dry

›Blood-streaked sputum suggests mucosal involvement

›Hemoptysis

›Ranges from blood-streaking to massive (>300 mL/24 h)

›Cavitary disease most common cause

›Constitutional symptom triad

›Fever

›Often low-grade, afternoon or evening predominance

›Drenching night sweats

›Unintentional weight loss

›Often >10% body weight

›Anorexia and fatigue

›Temporal course: insidious onset over weeks to months

›Subacute trajectory distinguishes TB from typical bacterial pneumonia

Respiratory symptoms

›Dyspnea

›Exertional limitation

›Progressive with advancing disease

›Pleuritic chest pain

›Pleural TB or empyema

›Orthopnea

›Pericardial TB consideration

Extrapulmonary symptom review

›Neurological

›Headache, confusion, neck stiffness

›TB meningitis — most severe form of extrapulmonary TB

›Focal neurological deficits

›Tuberculoma or spinal cord compression

›Musculoskeletal

›Back pain

›Pott disease (spinal TB) — most common form of skeletal TB

›Joint pain or swelling

›TB arthritis typically monoarticular

›Gastrointestinal

›Abdominal pain, diarrhea, ascites

›Peritoneal TB

›Dysphagia

›Oesophageal involvement rare

›Genitourinary

›Dysuria, hematuria, flank pain

›Renal TB — can present years after primary infection

›Sterile pyuria

›Classic clue for renal TB

›Lymphatic

›Painless cervical lymphadenopathy (scrofula)

›Most common form of extrapulmonary TB in high-income countries

›Cardiac

›Chest pain, dyspnea, orthopnea

›TB pericarditis with effusion

Exposure and epidemiological history

›Contact history

›Known or suspected TB case contact

›Duration and proximity of exposure

›Household contacts more at risk with smear-positive index case

›Congregate setting exposure

›Incarceration, homeless shelters, long-term care facilities

›Travel and immigration history

›Birth in or travel to high-prevalence countries

›Sub-Saharan Africa, Southeast Asia, South Asia, Eastern Europe

›Time since immigration

›Greatest risk of progression in first 2 years after exposure

›Prior TB and LTBI history

›Previous LTBI diagnosis or positive TST/IGRA

›Prior TB treatment history

›Prior incompletely treated TB

›Increases drug resistance risk

Risk factors

›Immune compromise

›HIV infection

›Strongest individual risk factor

›8-10% annual progression rate without ART

›CD4 <200: atypical presentations, lower lobe disease, disseminated risk

›TNF-alpha inhibitor use

›Screen with IGRA before initiating

›Post-transplant immunosuppression

›Systemic corticosteroids

›Comorbid conditions

›Diabetes mellitus: 7.5% attributable risk

›Poorer outcomes and slower sputum conversion

›Chronic kidney disease/dialysis

›Dose adjustments required for PZA and EMB

›Silicosis

›Synergistic risk with silica inhalation

›Chronic lung disease/COPD/bronchiectasis

›1.44-3.14-fold increased risk

›Social determinants

›Active smoking: 15.8% attributable risk

›Alcohol misuse: 9.8% attributable risk

›Malnutrition/low BMI: 26.9% attributable risk

›Malnutrition is both risk factor and consequence

›Healthcare worker occupational exposure

›Correctional facility staff, laboratory workers

03Physical Exam/exam68

Vital signs and general appearance

›Vital sign pattern

›Fever

›Low-grade, often 37.5-38.5 degrees Celsius

›Tachycardia

›Fever-driven or from haemodynamic compromise

›Weight and BMI

›Cachexia or recent significant weight loss

›Oxygen saturation

›SpO2 <92% triggers escalation

Respiratory examination

›Auscultation

›Apical crackles

›Classic finding in pulmonary TB

›Bronchial breath sounds

›Consolidation pattern

›Diminished breath sounds

›Pleural effusion

›Amphoric breathing

›Cavitary disease

›Percussion

›Dullness to percussion

›Pleural effusion or consolidation

›Upper zone dullness

›Cavitary disease with fibrosis

›Respiratory pattern

›Work of breathing

›Accessory muscle use

04Differential Diagnosis/ddx57

Pulmonary differentials

›Community-acquired pneumonia

›ICD-10: J18.9

›Shorter duration, acute onset distinguishes from TB

›Consider TB if no improvement after 7 days of antibiotics in high-risk patient

›Subacute presentation over weeks is key differentiator

›Lung malignancy

›ICD-10: C34.9

›Upper lobe mass, weight loss, hemoptysis can mimic TB

›Biopsy required to distinguish

›TB and malignancy can co-exist

›Non-tuberculous mycobacterial (NTM) infection

›ICD-10: A31.0

›AFB smear cannot distinguish from Mycobacterium tuberculosis

›Requires NAAT or culture speciation

›More common in immunocompromised, structural lung disease, elderly women

›Lung abscess

›ICD-10: J85.2

›Cavitary lesion; anaerobic organisms typical

›Usually lower lobe, TB typically upper lobe

›Aspergilloma

›ICD-10: B44.1

›Can colonise old TB cavities

›Aspergillus galactomannan positive

›Pulmonary sarcoidosis

›ICD-10: D86.0

›Bilateral hilar lymphadenopathy, non-caseating granulomas

›Can mimic TB clinically and radiographically

05Laboratory Tests/lt84

Microbiological diagnosis

›Sputum AFB smear microscopy

›Three sputum specimens (spot, early morning, spot)

›Sensitivity 45-80% for smear-positive pulmonary TB

›Specificity >99%

›Smear-negative TB occurs in 20-40% of cases

›Does not exclude TB; culture or NAAT required

›Cannot distinguish M. tuberculosis from NTM

›NAAT or culture needed for speciation

›Nucleic acid amplification test (NAAT)

›Xpert MTB/RIF (GeneXpert)

›WHO-endorsed first-line diagnostic

›Sensitivity 88% for smear-negative, culture-positive TB

›Specificity 99%

›Simultaneously detects rifampin resistance

›Result within 2 hours

›Xpert Ultra

›Higher sensitivity than Xpert MTB/RIF for smear-negative disease

›Slightly lower specificity

›Preferred for paucibacillary disease and HIV-positive patients

›Xpert MTB/XDR

›Detects resistance to INH, fluoroquinolones, ethionamide, amikacin

›Use when rifampin resistance detected on initial NAAT

›Mycobacterial culture

›Gold standard for diagnosis and susceptibility testing

›MGIT liquid culture: result in 10-21 days

›Solid media (Lowenstein-Jensen): 4-8 weeks

›Drug susceptibility testing (DST) on all positive cultures

›ATS/CDC/IDSA guideline recommendation

›Blood cultures (BACTEC MYCO/F Lytic) for miliary or disseminated TB

›Particularly important in HIV-positive patients

Immunological testing

›Tuberculin skin test (TST/Mantoux)

›Intradermal injection of purified protein derivative

›Read at 48-72 hours

›Positive: >=5 mm in HIV/immunocompromised, >=10 mm in moderate-risk, >=15 mm in low-risk

›False negative in active disease, malnutrition, immunosuppression, disseminated TB

›Negative TST does not exclude active TB

›False positive with BCG vaccination and NTM exposure

›IGRA preferred in BCG-vaccinated individuals

›Interferon-gamma release assay (IGRA)

›QuantiFERON-TB Gold Plus or T-SPOT.TB

›Sensitivity 80-90% for active TB

›Not affected by BCG vaccination

›Cannot distinguish latent from active TB

›Used alongside clinical and radiographic assessment

›Preferred over TST in immunocompromised patients

›ATS/CDC/IDSA guideline recommendation (Class I)

Routine laboratory investigations

›Complete blood count

›Anaemia of chronic disease

›Normocytic normochromic pattern

›Leukocytosis or leukopenia

›Monocytosis may be present

›Thrombocytopenia in disseminated disease

›Pancytopenia suggests miliary TB with bone marrow involvement

›Comprehensive metabolic panel

›Hepatic function (ALT, AST, bilirubin, ALP)

›Baseline required before initiating INH, RIF, PZA (all hepatotoxic)

›Repeat at 2, 4, 8 weeks then monthly during treatment

›Renal function (creatinine, eGFR)

›Dose adjustment required for PZA and EMB in renal impairment

›Electrolytes, glucose

›Hyponatraemia in miliary TB (SIADH)

›Serum uric acid

›PZA causes hyperuricaemia

›Baseline before initiating PZA

›Symptomatic gout managed with colchicine; hold PZA if severe

›HIV testing

›Mandatory in all newly diagnosed TB cases

›WHO and CDC recommendation

›CD4 count and HIV viral load if positive

›Guides ART initiation timing and rifabutin substitution

›Liver function monitoring

›Drug-induced liver injury (DILI) thresholds

›Hold hepatotoxic drugs if ALT >3x ULN with symptoms

›Hold if ALT >5x ULN regardless of symptoms

›Rechallenge in reverse order: RIF, INH, PZA

Cerebrospinal fluid analysis (if meningitis suspected)

›CSF parameters in TB meningitis

›Opening pressure: elevated (>200 mmH2O)

›Lymphocytic pleocytosis (100-500 cells/microL)

›Protein: elevated (1-5 g/L)

›Glucose: low (<2.5 mmol/L), CSF:serum glucose ratio <0.5

›AFB smear: sensitivity 10-40% only

›NAAT (Xpert Ultra) preferred: sensitivity 70-90% on CSF

›Culture: gold standard, takes weeks

›Large volumes (10-15 mL) improve sensitivity

06Diagnostic Tests/dt106

Scoring Systems

›TB screening and risk stratification tools

›WHO 4-symptom screen (cough, fever, night sweats, weight loss)

›Sensitivity 79%, specificity 50% for active TB in HIV-positive patients

›Negative screen makes active TB unlikely in HIV-positive patients

›PREDICT score

›Predicts TB vs bacterial pneumonia in ED presentations

›Incorporates HIV status, radiographic pattern, duration, exposure

›TB meningitis scoring

›British Infection Association criteria for TB meningitis

›Clinical score incorporating CSF parameters and risk factors

›Score >=12 has high specificity for TB meningitis

›Modified British Medical Research Council (BMRC) grading

›Grade 1: GCS 15, no focal deficits

›Grade 2: GCS 15 with focal deficits or GCS 11-14

›Grade 3: GCS <=10

›Guides prognosis and treatment intensity

›Drug-susceptible TB treatment monitoring

›Sputum culture conversion at 2 months

›Key predictor of treatment success

›Persistence of positive culture at 2 months: consider extended therapy

›WHO treatment outcome definitions

›Treatment success: cured + treatment completed

›Global treatment success rate approximately 87% for drug-susceptible TB

MRI

›CNS TB imaging

›MRI brain with gadolinium

›Modality of choice for TB meningitis and CNS tuberculoma

›Basal meningeal enhancement

›Most common finding in TB meningitis

›Highly characteristic pattern

›Communicating hydrocephalus

›Common complication of TB meningitis

›May require shunting

›Tuberculoma

›Ring-enhancing lesion with central hypointensity on T1

›Hypointense centre on T2 (caseating granuloma)

›Cerebral infarction

›Vasculitis complication — DWI restriction

›Spinal TB (Pott disease)

›MRI spine with gadolinium

›Modality of choice for vertebral TB

›Disc space involvement with adjacent vertebral destruction

›TB typically involves >1 disc space (vs pyogenic infection)

›Paraspinal abscess

›Psoas abscess tracking

›Epidural extension causing cord compression

›Gibbus deformity

›Kyphotic deformity from anterior vertebral collapse

CT

›Chest CT

›Indications for chest CT over plain radiograph

›CXR negative but high clinical suspicion

›Extent of disease quantification

›Pre-surgical or bronchoscopic planning

›Upper lobe distribution

›Posterior segment upper lobes and superior segments lower lobes

›Tree-in-bud pattern indicating endobronchial spread

›Cavitary disease

›Thick-walled upper lobe cavities with surrounding infiltrate

›Highly infectious: priority airborne isolation

›Miliary pattern

›1-3 mm randomly distributed micronodules bilaterally

›Haematogenous dissemination

›Mediastinal and hilar lymphadenopathy

›Low-attenuation centres (necrotic nodes) characteristic of TB

›Contrast CT reveals rim enhancement

›CT abdomen/pelvis

›Peritoneal TB

›Ascites with peritoneal nodularity or thickening

›Omental caking pattern

›Lymphadenopathy with central necrosis

›Mesenteric or retroperitoneal nodes

›Solid organ involvement

›Hepatic or splenic granulomas

›Renal involvement: cortical granulomas, calcification

›CT head (non-contrast)

›Initial rapid assessment before LP

›Exclude mass effect prior to lumbar puncture

›Hydrocephalus detection

›Ventriculomegaly

›Calcified granulomas

›Prior CNS TB

Ultrasound

›Pleural ultrasound

›Pleural effusion detection

›More sensitive than CXR for small effusions

›Guidance for thoracentesis

›Marked under real-time guidance preferred

›Echogenic or complex effusion

›Suggests exudate, TB pleuritis, or empyema

›Pleural thickening or fibrin stranding

›TB pleuritis pattern

›Abdominal ultrasound

›Ascites detection and characterisation

›Septated or echogenic: peritoneal TB pattern

›Lymphadenopathy with central necrosis

›Mesenteric and retroperitoneal nodes

›Hepatosplenomegaly

›Miliary disease

›Guidance for paracentesis

›Diagnostic peritoneal fluid in peritoneal TB

›Cardiac ultrasound (echocardiography)

›TB pericarditis with effusion

›Quantify effusion size

›Assess tamponade physiology: diastolic RV collapse, IVC plethora

›Guidance for pericardiocentesis

›Preferred approach for drainage

›Constrictive pericarditis assessment

›Late complication: pericardial thickening, septal bounce

07Disposition/dispo45

Airborne isolation requirements

›Inpatient airborne isolation criteria

›All patients with suspected or confirmed active pulmonary TB

›AIIR (negative-pressure room) mandatory

›N95 or higher for all entering staff

›Duration of isolation

›Continue until three consecutive sputum AFB smear-negative results

›Clinical improvement on treatment for minimum 2 weeks

›Infectiousness declines rapidly: <1% of pretreatment level after 14-21 days of effective therapy

›NAAT-negative result may allow earlier de-isolation if clinical probability is low

›JAMA Intern Med 2018: rapid NAAT testing reduced isolation duration significantly

Admission indications

›Mandatory admission

›Critically ill with respiratory failure, haemodynamic instability

›ICU level care for ARDS, massive haemoptysis, or septic shock

›TB meningitis, miliary TB, TB pericarditis

›Complex extrapulmonary TB requiring inpatient monitoring

›Inability to tolerate oral medications

›IV alternative formulations limited for TB drugs

›Social circumstances precluding outpatient treatment

›Homelessness, substance use disorder without supports

›No reliable DOT in community

›Drug-resistant TB (MDR-TB or XDR-TB)

›Complex regimens requiring close monitoring

Discharge criteria and outpatient management

›Criteria for outpatient initiation of therapy

›Clinically stable with no severe complications

›Adequate social supports and housing

08Treatment/t107

Airborne precautions (parallel to treatment initiation)

›Respiratory isolation and infection control

›AIIR placement before treatment initiation

›N95 respirator for all entering staff

›Patient education on respiratory hygiene

›Cover cough, wear surgical mask when leaving room

›Sputum induction in negative-pressure booth only

›Not in general areas

First-line regimen for drug-susceptible TB

›Standard 6-month RIPE regimen (ATS/CDC/IDSA 2016, updated 2025)

›Intensive phase: 2 months of HRZE (daily)

›Isoniazid (H/INH): 5 mg/kg/day orally (max 300 mg/day)

›Pyridoxine (B6) 25-50 mg/day co-administered to prevent peripheral neuropathy

›Rifampin (R/RIF): 10 mg/kg/day orally (max 600 mg/day)

›Potent CYP450 inducer — extensive drug interactions

›Pyrazinamide (Z/PZA): 25-35 mg/kg/day orally (max 2,000 mg/day)

›Reduces to 15-30 mg/kg if eGFR <30 mL/min

›Ethambutol (E/EMB): 15-25 mg/kg/day orally

›Discontinue once INH and RIF susceptibility confirmed

›Continuation phase: 4 months of HR (daily)

›Isoniazid 5 mg/kg/day (max 300 mg/day)

›Rifampin 10 mg/kg/day (max 600 mg/day)

›Extend to 7 months total if cavitary disease AND 2-month culture positive

›Alternative 4-month regimen (NEJM 2022 TRUNCATE-TB / ATS 2025 update)

›8 weeks: rifapentine 1,200 mg + moxifloxacin 400 mg + INH 300 mg + PZA (weight-based) daily

›Non-inferior to 6-month regimen for drug-susceptible TB

›9 weeks: rifapentine 1,200 mg + moxifloxacin 400 mg + INH 300 mg daily

›QTc monitoring required with moxifloxacin

›Not recommended for CNS, bone/joint, or disseminated TB

›Directly observed therapy (DOT)

›Preferred delivery method per ATS/CDC/IDSA guidelines

›Reduces default and acquired resistance

›Video directly observed therapy (vDOT) acceptable alternative

›Equivalent outcomes to in-person DOT

Drug-resistant TB treatment

›Multidrug-resistant TB (MDR-TB): resistant to at least INH and RIF

›BPaL regimen (bedaquiline + pretomanid + linezolid) — TB-PRACTECAL and ZeNix trials

›Bedaquiline 400 mg daily x 2 weeks, then 200 mg 3x/week x 22 weeks

›QTc monitoring at baseline, 2, 4, 8, 12, 24 weeks

›Discontinue if QTc >500 ms

›Pretomanid 200 mg daily x 26 weeks

›Linezolid 600 mg daily (reduce to 300 mg if toxicity)

›Monitor for myelosuppression and peripheral neuropathy

›Duration: 6 months; WHO-endorsed shorter regimen for pre-XDR TB

›Infectious disease specialist mandatory

›Pre-XDR-TB (MDR + resistance to fluoroquinolone)

›BPaL with optimised background regimen

›Clofazimine, cycloserine, delamanid as additional agents

›QTc prolongation risk with bedaquiline, clofazimine, and fluoroquinolones combined

›Serial ECG monitoring mandatory

Adjunctive corticosteroid therapy

›TB meningitis (Class I recommendation)

›Dexamethasone 0.4 mg/kg/day IV for 4 weeks, then taper over 4 weeks

›Reduces mortality and severe disability

›Start simultaneously with anti-TB therapy

›Equivalent to prednisolone 40-60 mg/day

›Oral conversion when tolerating orally

›TB pericarditis

›Prednisolone 60 mg/day x 4 weeks, taper over 11 weeks total

›Reduces constrictive pericarditis development

›Evidence from IMPI trial: significant reduction in hospitalisation

›Endobronchial TB with airway compression

›Short-course prednisolone 40 mg/day x 4 weeks

›Reduces fibrosis and stenosis risk

Symptom and adverse effect management

›Drug-induced hepatitis monitoring and management

›Transaminases at baseline, 2, 4, 8 weeks then monthly

›Hold hepatotoxic drugs if ALT >3x ULN with symptoms or >5x ULN

›Rechallenge sequence after DILI resolution

›Rechallenge RIF first, then INH, then PZA

›PZA may be permanently omitted if DILI severe

›Peripheral neuropathy prevention

›Pyridoxine 25-50 mg daily with all INH-containing regimens

›Higher dose (100 mg) for diabetics, alcohol use, malnutrition

›Hyperuricaemia

›PZA-induced: asymptomatic hyperuricaemia does not require treatment

›Symptomatic gout: colchicine 0.6 mg twice daily

›Hold PZA only if severe gouty arthritis

›Optic neuritis (EMB toxicity)

›Baseline visual acuity and colour vision before EMB

›Monthly monitoring for duration of EMB use

›Discontinue EMB immediately if visual symptoms develop

›Rifampin drug interactions

›Reduces warfarin effect: INR monitoring, dose adjustment needed

›Reduces oral contraceptive efficacy: alternative contraception required

›Reduces methadone levels: opioid withdrawal risk

›Reduces ARV levels: rifabutin substitution for HIV patients on most ART

HIV-TB co-infection treatment

›ART initiation timing in TB

›CD4 <50: initiate ART within 2 weeks of TB treatment start

›Reduces mortality significantly (CAMELIA, STRIDE trials)

›CD4 50-500: initiate ART within 8-12 weeks

›TB meningitis exception: delay ART 4-8 weeks to reduce IRIS risk

›CNS IRIS associated with early ART in TB meningitis

›Rifamycin selection in HIV-TB

›Rifabutin 300 mg/day preferred over rifampin for most ART regimens

›Less potent CYP3A4 inducer

›Adjust dose based on concurrent ARV (150 mg if on ritonavir-boosted PI)

›Dolutegravir dose increase to 50 mg twice daily when on rifampin

›ATS/CDC/IDSA and HIV guideline recommendation

›Immune reconstitution inflammatory syndrome (IRIS)

›Paradoxical IRIS: worsening TB symptoms 2-8 weeks after ART initiation

›Continue ART and TB treatment in most cases

›Prednisolone 1.5 mg/kg/day for severe IRIS

›Taper over 4 weeks

Nutritional and supportive care

›Nutritional support

›High-protein, calorie-dense diet throughout treatment

›Malnutrition accounts for 26.9% of attributable risk and delays recovery

›Vitamin supplementation beyond pyridoxine if deficiency present

›Vitamin D sufficiency associated with improved outcomes

›Alcohol cessation

›Mandatory throughout treatment

›Alcohol increases hepatotoxicity risk of INH, RIF, and PZA substantially

09Special Populations/sp87

Pregnancy

›Maternal and foetal risk considerations

›Active TB in pregnancy associated with preterm birth, low birth weight, neonatal TB

›Untreated TB more dangerous to mother and foetus than treatment

›Vertical transmission of TB uncommon but possible

›Congenital TB has high neonatal mortality

›Treatment in pregnancy

›Standard first-line HRZE regimen generally safe in pregnancy

›INH, RIF, and EMB considered safe (WHO recommendation)

›Pyridoxine 25-50 mg/day mandatory with INH in pregnancy

›Pyrazinamide (PZA)

›WHO recommends PZA inclusion in pregnancy (2022 update)

›Previously withheld due to limited safety data; now recommended

›Streptomycin contraindicated

›Ototoxicity and nephrotoxicity risk to foetus

›Aminoglycosides (MDR-TB): teratogenic

›Avoid if possible; specialised guidance required

›Fluoroquinolones: avoid in first trimester

›Risk of arthropathy; use only if benefits outweigh risks

›Monitoring in pregnancy

›Baseline hepatic function; repeat monthly

›Pregnancy increases hepatotoxicity risk

›Close obstetric and infectious disease co-management

›MDR-TB in pregnancy requires multidisciplinary team

›Breastfeeding

›TB drugs pass into breast milk in small concentrations

›Generally considered safe for breastfed infants

›INH prophylaxis for neonate may be indicated if mother has active TB

›Neonatal pyridoxine supplementation if INH-exposed via breast milk

Geriatric

›Atypical presentations in elderly

›Classic triad (cough, fever, night sweats) less common in elderly

›Fatigue, confusion, weight loss may be only symptoms

›Higher risk of extrapulmonary and disseminated TB

›Reactivation risk from decades-old latent infection

›Overlap with malignancy, other chronic diseases complicates diagnosis

›Drug metabolism and toxicity

›Increased hepatotoxicity risk with INH and PZA

›More frequent liver function monitoring: every 2 weeks initially

›Lower threshold for dose reduction or drug substitution

›EMB optic toxicity risk increased

›Monthly visual acuity and colour vision testing mandatory

›Renal impairment (age-related)

›eGFR-based dose adjustment for PZA and EMB

›PZA: 25-30 mg/kg 3x/week if eGFR <30 mL/min

›Drug-drug interactions in polypharmacy

›Rifampin CYP450 induction affects many common medications

›Review all concurrent medications with pharmacist

›Cognitive considerations

›Cognitive impairment affects DOT adherence

›Caregiver-assisted DOT may be required

›INH-associated encephalopathy

›Rare; higher dose pyridoxine protective

Pediatrics

›Clinical presentation in children

›Younger children (<5 years) have highest risk of severe/disseminated disease

›Miliary TB and TB meningitis most dangerous in under 5s

›Non-specific symptoms: failure to thrive, fever, fatigue

›Cough less prominent than adults; hilar adenopathy more common

›Primary complex (Ghon focus + hilar adenopathy)

›Classic radiographic pattern in children

›Diagnosis in children

›Sputum difficult to obtain in young children

›Gastric aspirate on 3 consecutive mornings (early AM)

›Induced sputum preferred if child >5 years

›NAAT on gastric aspirate: sensitivity 55-75% in children

›AFB smear: low sensitivity in children (paucibacillary disease)

›Contact investigation essential

›Identify index case for susceptibility testing

›Paediatric dosing (weight-based)

›Isoniazid: 10-15 mg/kg/day (max 300 mg)

›Children metabolise INH faster than adults

›Rifampin: 15-20 mg/kg/day (max 600 mg)

›Pyrazinamide: 30-40 mg/kg/day (max 2,000 mg)

›Ethambutol: 20 mg/kg/day (max 1,200 mg)

›Avoid in young children unable to report visual symptoms (<5 years if possible)

›Pyridoxine: 1-2 mg/kg/day with INH

›Mandatory in malnourished or breastfed infants

›TB meningitis in children

›High-dose INH: 15-20 mg/kg/day for CNS penetration

›Standard 10 mg/kg has limited CNS penetration

›Dexamethasone mandatory for all grades of TB meningitis in children

›0.4 mg/kg/day x 4 weeks, then taper

›Extended therapy 9-12 months for CNS TB

›BCG vaccination

›Neonatal BCG protects against severe/disseminated TB in infants

›80% efficacy against TB meningitis and miliary TB

›Does not reliably protect against pulmonary TB in adolescents/adults

›BCG vaccination causes TST positivity (use IGRA for testing)

›BCG contraindicated in immunocompromised children (HIV-positive, severe combined immunodeficiency)

10Background/b94

Epidemiology

›Global burden

›Leading infectious cause of death worldwide from a single pathogen

›Approximately 10.6 million new TB cases in 2022 (WHO Global TB Report 2023)

›1.3 million TB deaths in 2022 (excluding HIV-TB deaths)

›Additional 167,000 deaths in HIV-positive people with TB

›Approximately one-third of cases go undiagnosed globally

›Cochrane review estimate

›30 high-burden countries account for 87% of new TB cases

›Led by India, Indonesia, China, Philippines, Pakistan

›North American epidemiology

›Incidence in US: approximately 7,500 cases/year

›Rate 2.3 per 100,000 (CDC 2022)

›80% of US cases occur in foreign-born persons

›Or in US-born persons with risk factors (HIV, congregate settings)

›Reactivation TB accounts for >80% of cases in low-incidence settings

›Most cases arise from latent TB reactivation, not recent transmission

›Mortality and morbidity

›Untreated active TB mortality: 45-65% at 5 years

›HIV-TB co-infection mortality significantly higher

›Miliary TB mortality: 47-58% in adults even with treatment

›TB meningitis: 20-30% mortality; 50% survivors have neurological sequelae

›TB pericarditis: 14-34% mortality without treatment

Pathophysiology

›Transmission

›Airborne transmission via aerosolised droplet nuclei (1-5 microns)

›Generated by coughing, sneezing, speaking, singing

›Infectious nuclei remain airborne for hours

›Infectious dose: as few as 1-10 bacilli to initiate infection

›Smear-positive patients most infectious

›Cavitary disease produces highest bacterial burden and infectivity

›Primary infection and latent TB

›Inhaled bacilli deposited in alveoli

›Phagocytosed by alveolar macrophages

›Macrophages unable to eliminate M. tuberculosis

›Bacilli survive and replicate intracellularly

›Granuloma formation (Ghon focus)

›T-cell mediated immune response walls off bacilli

›Latent TB infection (LTBI): viable dormant bacilli contained by immune response

›5-10% lifetime risk of reactivation in immunocompetent host

›8-10% annual risk in HIV-positive without ART

›Disease mechanisms

›Reactivation

›Immunosuppression disrupts granuloma integrity

›Bacilli re-emerge and multiply

›Caseating necrosis with cavity formation

›Pulmonary cavitation

›Liquefactive necrosis releases vast numbers of bacilli

›Bacilli access airways for sputum and airborne transmission

›Haematogenous dissemination

›Miliary TB: lymphohaematogenous seeding of all organs

›Occurs with massive bacillaemia in immunocompromised hosts

›TB meningitis pathogenesis

›Sub-ependymal Rich foci rupture into subarachnoid space

›Basilar meningitis with vasculitis, hydrocephalus, cranial nerve palsies

›Drug resistance mechanisms

›INH resistance: most commonly katG mutation (catalase-peroxidase)

›Also inhA promoter mutation (lower-level resistance)

›RIF resistance: rpoB mutations in RNA polymerase beta subunit

›RIF resistance is a proxy marker for MDR-TB

›Amplified resistance from inadequate treatment

›Monotherapy, subtherapeutic doses, poor adherence drive resistance

Therapeutic Considerations

›Treatment duration and design principles

›Four-drug intensive phase eliminates susceptible bacilli rapidly

›Prevents selection of resistant mutants

›Continuation phase targets persister bacilli (semi-dormant)

›Sterilizing effect of RIF and PZA prevents relapse

›DOT increases treatment completion rates substantially

›16-49% of patients do not complete therapy without supervision

›Hepatotoxicity risk stratification

›All three first-line drugs (INH, RIF, PZA) are hepatotoxic

›Combined hepatotoxicity risk with all three drugs

›Higher risk: age >35, baseline liver disease, alcohol use, HIV

›Pre-existing hepatitis B or C: most significant hepatotoxicity risk

›Drug-induced liver injury (DILI) management

›See DILI threshold and rechallenge protocol in Treatment section

›Drug interactions with rifamycins

›Rifampin is the most potent CYP450 inducer of all anti-TB drugs

›Accelerates metabolism of warfarin, OCP, methadone, protease inhibitors

›Dolutegravir requires dose increase to 50 mg twice daily

›Rifabutin (weaker CYP3A4 inducer) substituted in HIV patients on certain ART

›Rifabutin 150 mg/day if on ritonavir-boosted PI

›Rifabutin 450-600 mg/day if on efavirenz

›QTc monitoring for newer/second-line agents

›Bedaquiline, delamanid, moxifloxacin, clofazimine all prolong QTc

›Serial ECG monitoring at baseline and throughout treatment

›Avoid combining multiple QT-prolonging agents if possible

›Threshold for drug discontinuation: QTc >500 ms

›Cardiology consultation for prolonged QTc

›Treatment success monitoring

›Sputum culture conversion at 2 months: key endpoint

›Expected in >80% of drug-susceptible TB on standard regimen

›Clinical response: fever and constitutional symptoms improve within 2 weeks

›Infectiousness <1% of pretreatment level after 14-21 days effective treatment

›CXR at 2 months and end of treatment

›Radiographic improvement lags behind clinical and microbiological response

11Patient Discharge Instructions/pdi50

copy discharge instructions

›What you have been diagnosed with

›Active tuberculosis (TB) — a bacterial infection of the lungs (and sometimes other organs) caused by Mycobacterium tuberculosis

›TB is curable with complete treatment

›You must take all medications for the full course to be cured

›Your medications

›You have been prescribed a combination of anti-TB drugs (typically 3-4 medications)

›Take all medications exactly as prescribed — missing doses can cause your TB to become drug-resistant and much harder to treat

›Take your medications with food to reduce stomach upset

›Do not take antacids, milk, or calcium supplements within 2 hours of your TB medications

›Rifampin/rifabutin will turn your urine, sweat, saliva, and tears orange-red

›This is harmless and expected

›Soft contact lenses may be permanently stained — avoid wearing them

›Do not drink alcohol during the entire course of treatment

›Alcohol combined with your TB medications significantly increases the risk of liver damage

›If you take oral contraceptives (birth control pills), they will not work well while you are on rifampin

›Use an alternative form of contraception (condoms, intrauterine device) throughout treatment

›Directly observed therapy (DOT)

›A public health nurse or health worker will assist you in taking your medications

›This is called directly observed therapy (DOT)

›Your first DOT appointment has been arranged

›You must keep this appointment — your treatment depends on it

›Video DOT (taking your medications on a video call) may be available

›Preventing spread to others

›TB is spread through the air when you cough, sneeze, or talk

›Cover your mouth and nose with a tissue when you cough or sneeze

›Wear a surgical mask when in the same room as others until your doctor tells you that you are no longer infectious

›Avoid public places, crowded settings, and public transport until your TB team tells you it is safe

12References/r39

Guidelines and key sources

›ATS/CDC/IDSA 2016 guidelines: Treatment of drug-susceptible TB

›Nahid P et al. CID 2016

›Foundation guideline for standard HRZE regimen

›ATS/CDC/ERS/IDSA 2025 update: Treatment of drug-susceptible and drug-resistant TB

›Saukkonen JJ et al. AJRCCM 2025

›Includes 4-month rifapentine-moxifloxacin regimen recommendation

›ATS/CDC/IDSA 2017 guidelines: Diagnosis of TB in adults and children

›Lewinsohn DM et al. CID 2017

›IGRA and NAAT recommendations

›NTCA 2024: Guidelines for respiratory isolation for pulmonary TB

›Shah M et al. CID 2024

›Isolation duration criteria with NAAT-guided de-isolation

Landmark trials and systematic reviews

›Xpert MTB/RIF and Xpert Ultra for TB screening

›Shapiro AE et al. Cochrane 2021

›Xpert Ultra sensitivity 88% for smear-negative, culture-positive TB

›TB meningitis management guideline

›Donovan J et al. Lancet Infect Dis 2026

›Dexamethasone adjunct therapy evidence

›Miliary TB outcomes

›Sharma SK, Mohan A. Microbiology Spectrum 2017

›ARDS mortality 47-58% in miliary TB

›TB and HIV co-infection management

›IDSA/OARAC Adult and Adolescent OI Guidelines 2025

›ART timing and rifabutin dosing

›JAMA Internal Medicine 2018: Rapid NAAT and isolation duration

›Chaisson LH et al. JAMA Intern Med 2018

Evidence & Review